2,6-bis(thiomethyl)-4-methyl anisole

ABSTRACT

These compounds are useful as microbiocides.   A class of compounds having the structure:

Harold Marvin Foster Park Forest, 111.

Oct. 13, 1969 Nov. 16, 1971 The Sherwin-Williams Company Cleveland, OhioInventor Appl. No. Filed Patented Assignee 2,6-BIS('IHIOMETHYL)-4-METHYLANISOLE 3 Claims, No Drawings SEARCH Rom [56] References Cited UNITEDSTATES PATENTS 3,541,157 11/1970 Hayetal 260/609FX PrimaryExaminerCharles B. Parker Assistant ExaminerD. R. PhillipsAttorneys-Richard G. Smith, Richard J. Lustig and Lowell G.

Wise

ABSTRACT: A class of compounds having the structure:

| CH1S(CH;).,H

ghere n is an integer from 0 to 3.

7 These compounds are useful as microbiocides.

DESCRIPTION This invention relates to thiobenzenoid compounds which area, a'-dithio derivatives of 2-methoxy-S-methyl-m-xylene. In particular,mercapto and thioether compounds having activity againstmicro-organisms, especially fungi, are provided.

The thiobenzenoid compounds of this invention can be synthesized from2,6-bis(hydroxymethyl)-4-methylanisole, which is described by Ullmannand Brittner in Ber., 42, 2539( 1909). This starting material is used tomake an intermediate compound, 2-methoxy-5-methyl-m-xylylene dichlorideby reaction with thionyl chloride. This method is described in detail inmy copending US. Pat. application, Ser. No. 865,945, filed concurrentlyherewith and entitled 2- Methoxy-S-methyl-m-xylylene dichloride,incorporated herein by reference.

To prepare the thioether species of this invention, the dichlorideprecursor is reacted by heating with a lower n-alkyl thiol in thepresence of a base, according to the following reaction:

where x is an integer from 1 to 3.

The dithiol species can be prepared by a two step process in which thesame precursor, 2-methoxy-5-methyl-m-xylylene dichloride, is reacted byheating with thiourea in alcohol solution to convert the precursor to asecond intermediate, 2- methoxy-S-methyl-mxylylenebis( isothiuroniumchloride). This reaction is described in my copending US. Pat.application, Ser. No. 865,978 filed concurrently herewith and entitled2-Methoxy-5-methyl-m-xylylenebis(isothiuronium chloride)," which isincorporated herein by reference.

The conversion of the second intermediate to the dithiol derivative isobtained by heating the isothiuronium chloride compound with a sodiumcarbonate, according to the following reaction:

The invention is demonstrated by the following examples in which theunits are parts by weight unless otherwise stated. The inventive conceptis not limited by these examples.

EXAMPLE I To a refluxing solution of 334 parts by weight (4.4 mols) ofl-propanethiol, 176 parts sodium hydroxide (4.4 mols) and 1632 partsethanol was added a slurry of 438 parts (2 mols) of2-methoxy-5-methyl-m-xylylene dichloride in 1224 parts ethanol. Thisaddition was carried out incrementally over a period of -30 minutes withagitation of the reaction mixture. The heating under reflux at about 80C. was continued for about 6 hours, and the mixture was filtered hot toremove inorganic salts. The volative liquid was removed by vacuumdistillation at 100 mm. Hg. The residue was dissolved in benzene, washedwith water and diluted aqueous NaOH solution, and dried over anhydrouscalcium sulfate to remove the solvent.

A residual oil was recovered and vacuum distilled to yield fivefractions. Table I shows the boiling range of each fraction, the weightof the fraction, estimated minimum purity by vapor phase chromatographymethods (GLC) and estimated minimum purity by thin layer chromatography(TLC).

TABLE I Wt. percent Fraction Boiling Pressure GLC TLC Parts by 0. rangeC.) (mm. Hg) assay assay weight 1.. 30. 6-26 0. 4 Discarded 0!) 2" 147.0151 0. 46 83 95 122 3.. 161. 0-153 0. 40 42 4 1150. 0-163 0. 38 97 95176 b. 150. 0156 0. 35 87 95 15 EXAMPLE ll A mixture of 372 parts (1mol) of 2-methoxy-5-methyl-mxylylenebis(isothiuronium chloride), 2l0parts (2 mols) anhydrous sodium carbonate, and 3,000 parts water washeated under reflux for about 1.5 hours, then cooled to ambienttemperature. The reaction mixture was extracted with 2,230 partschlorofonn three times. The chloroform extract solution was combined anddried by passing through anhydrous calcium sulfate. The chloroform wasremoved by heating the solution and drying under vacuum. The residualoil was distilled under reduced pressure to give three fractions. TableII shows the boiling range, of each fraction, the weight of thefraction, estimated minimum purity by vapor phase chromatography methods(GLC), and estimated minimum purity by thin layer chromatography (TLC).

TABLE II Wt. percent Fraction Weight Boiling Pressure TLC (lLC N0. partsrange 0.) (mm. Hg) assay assay l (1 121. 11-125 0. 3 97 2 95 118. 6-1230. 23 99 9B 3 11!). 0-12l O. 23 "8 The total yield was 158 parts of2-methoxy-5-methyl-m-xylylene-dithiol (74.5 percent of theory). Infraredand nuclear magnetic resonance studies corroborated the structure, andthe following microanalyses were determined:

Calculated for: G l-1 0s,: C, 56.04; H, 6.58; S, 29.92 Found: C, 56.31;H, 6.47; S, 29.91.

UTILITY Agar Plate Tests :ads /z-inch diameter). After evaporation ofthe carrier liquid, the pads were placed on the agar plates. Both padsand plates were inoculated with a spore suspension of the test fungi,Pullularia pullulans (p.p.) Cladosporium sphaerospermum shown in tableIV, in which the zone of inhibition is given. The test organismsincluded: Staphylococcus aureus (S.a.), Aerobacter aerogenes (A.a.),Pseudomonas aeruginosa (Pa), Torula uiilis (T.ul), Saccraromycescerevisiae (S.c.), Penicilli- (c.s.), and Aspergillus niger (A.n.). Thedithiol sample was 5 P -L Chaewmium 8 -B), Z P compared to acommercially used fungicide, Captan. After a "igricans 4 Pullulam -P-Land Asperglllus period of standard incubation, the pads and agar plateswere g examined to determine growth of fungus on the pad and to In usingthe novel compounds of this invention as microbiomeasure the zone width(millimeters) of growth inhibition in CideS, the pp i can y Severalmethods- A 2 y the agar plate b d h periphery fth smaller treated 10effective amountof the active compound may be app ie to The result oftheagar plate tests are Shown in table "L the loci of the micro-organism bydirect contact of the com TABLE TIL-FUNGICIDAL ACTIVITY Test organism P.p. C. a. A. n. Cone,

wt. Zone Growth Zone Growth Zone Growth Compound percent (mni.) on pad(mm.) on pad (mm.) on pad Dithiol i 7 0 l6 0 7 0 0.1 3 0 2 .01 0 0 0Captan 0. 1 1O 0 17 0 11 0 0. 01 5 0 s 0 4 0 Control 0 0 0 0 TABLE IVBiocidal zone of inhibition (mm.)

Compound S. a. A. a. P.a. '1'.u. S. c. P. e. (lg. R. H. P. p. A. n.

Dithiol 0 0 0 1 1 6 3 4 5 4 Negative control 0 0 0 0 0 O 0 0 0 0Hoxnchlorophono 6 4 2 1 1 1 1 3 2 2 Textile Protection pound in an inertcarrier also, the compound may be incororated direct] in a fiber film orcoatin Desized cotton sheeting was treated with 2,6-bis(n-propylp y gmercaptomethyl)-4-methylanisole in an amount sufficient to A tit ishAgent deposit 1 part of the compound per 100 parts of cotton. Thecarrier was evaporated and the samples were placed on a ASlh/er cleahlhgPaste ph h was formulated dextrose-mineral salts agar plate in a sterileenvironment. The 'hethoxy's'methylm'xylylehedlthlol as 3 Pi? of the f hpsamples were inoculated with a suspension of mixed fungi 40 "9 P thestahdahd comPosmoh cohtammg spores (AATC 576.l The treated samples andnegative condlthlol cofhpouhfjv Improved {amlsh reslstflhce for w metaltrols were observed at three and seven day intervals. No was ohthmedwith the cofhposmoh cohtalhmg the growth was noted on the treatedsamples in this test; however, new dhhlol Q P h as an ahmamlshagemtheuntreated control material had fungi growth. This in- Whlle h t h h h yspeclfic exam dicates that the compound a b d to increase h k ples,there is no intent to limit the inventive concept thereby. gevity oftextiles. I claim:

ll. As a composition of matter a compound having the struc- BiologicalActivity ture formula: z 1) H A series of tests was conducted todemonstrate the biologi- I cal activity of2-methoxy-5-methyl-m-xylylenedithiol against 10 species of bacteria,yeasts and fungi. The test procedure was similar to the agar plate testsabove. The test compounds HISwHMH were dissolved in an organic solventat 1 percent concentration, and a measured amount was applied to afilter paper disc. wher? h Integer from f The dried paper disc wassterilized with ethylene oxide and the 2 The composition of claim 1wherein the compound is 2,6- disc was placed on the special agar seededwith the test organbi5(n-propylmercaptomethyl)-4-methylaniSOle. ism. Astandard incubation period was used for the control, 3 Th composition fl i t h i h compound i 2- dithiol sample and a comparative commercialmicrobiocidal methQXy-S-methyl-my ylenedithiolcompounds,hexachlorophene. The results for the tests are a a

2. The composition of claim 1 wherein the compound is2,6-bis(n-propylmercaptomethyl)-4-methylanisole.
 3. The composition ofclaim 1 wherein the compound is 2-methoxy-5-methyl-m-xylylenedithiol.